title: Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. Groupe D'etude des Tumeurs à Calcitonine.
abstract: Germline mutations of the RET proto-oncogene are responsible for multiple endocrine neoplasia type 2, including multiple endocrine type 2A (MEN 2A), type 2B (MEN 2B), and familial medullary thyroid carcinoma. The relationship between specific mutations and syndromic features has been established. In particular, the risk for pheochromocytoma and hyperparathyroidism (HPT) in MEN 2A patients is clearly associated with the presence of the RET mutation at a specific position, i.e. at codon 634. Also, a correlation between a specific mutation, C634R, and the development of HPT has been suggested but is still controversial. To further investigate the relationship between specific mutations of codon 634 and the development of HPT, we studied a population of 188 individuals, carrying mutations at codon 634, namely C634R (65 patients belonging to 10 families), C634Y (80 patients belonging to 11 families), or the less frequent codon 634 mutations [i.e. C634S, C634F, C634G, or C634W (43 patients belonging to 9 families)]. In this series of patients, we defined an overall HPT prevalence of 19.1% and found that this prevalence did not vary significantly, with respect to the nature of the mutation. However, irrespective of the particular mutation, the prevalence of HPT showed a high interfamilial variability. The statistical model that best fitted with the observed data was in favor of the heterogeneity of the risk for HPT, with 40% of the families showing an HPT risk of 34% and 60% of the families showing an HPT risk of 9%. In addition, our study clearly demonstrated that HPT could be an early component of the disease and provided the first estimate of age-specific and mutation-specific HPT penetrance in individuals with mutations of codon 634 of the RET proto-oncogene.
authors.affiliation: Laboratoire de Génétique, Hôpital Edouard Herriot, Lyon, France.
authors.forename: I
authors.initials: I
authors.lastname: Schuffenecker
authors.forename: M
authors.initials: M
authors.lastname: Virally-Monod
authors.forename: R
authors.initials: R
authors.lastname: Brohet
authors.forename: D
authors.initials: D
authors.lastname: Goldgar
authors.forename: B
authors.initials: B
authors.lastname: Conte-Devolx
authors.forename: L
authors.initials: L
authors.lastname: Leclerc
authors.forename: O
authors.initials: O
authors.lastname: Chabre
authors.forename: A
authors.initials: A
authors.lastname: Boneu
authors.forename: J
authors.initials: J
authors.lastname: Caron
authors.forename: C
authors.initials: C
authors.lastname: Houdent
authors.forename: E
authors.initials: E
authors.lastname: Modigliani
authors.forename: V
authors.initials: V
authors.lastname: Rohmer
authors.forename: M
authors.initials: M
authors.lastname: Schlumberger
authors.forename: C
authors.initials: C
authors.lastname: Eng
authors.forename: P J
authors.initials: PJ
authors.lastname: Guillausseau
authors.forename: G M
authors.initials: GM
authors.lastname: Lenoir
mesh_terms: D000328:Adult; D000375:Aging; D003062:Codon; D029721:Drosophila Proteins; D006801:Humans; D006961:Hyperparathyroidism / Q000453:epidemiology / Q000235:genetics*; D008875:Middle Aged; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics*; D009154:Mutation; D019683:Penetrance; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012307:Risk Factors
chemical_list: D003062:Codon; D029721:Drosophila Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila